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MSK‐1 mediated Histone H3 phosphorylation is critical for ethanol‐induced inhibition of IL‐2 gene transcription in CD4+ T lymphocytes
Author(s) -
Ghare Smita,
JoshiBarve Swati,
McClain Craig,
Barve Shirish
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.756.19
Subject(s) - histone h3 , phosphorylation , chromatin immunoprecipitation , h3k4me3 , histone , microbiology and biotechnology , biology , histone methyltransferase , histone methylation , regulation of gene expression , histone h2a , gene expression , chemistry , promoter , biochemistry , dna methylation , gene
Immune suppression due to decreased CD4+ T cell function is a significant pathogenic component of multiple diseases including alcoholism, HIV infection and aging; however, the underlying mechanisms are not yet fully understood. We have previously shown that immunosuppressive effects of alcohol involve a decrease in the expression of interleukin‐2 (IL‐2), which critically regulates T cell proliferation, clonal expansion and homeostasis. In the present study we investigated the role of ethanol‐induced promoter histone modifications in the context of dysregulated IL‐2 gene expression. Chromatin immunoprecipitation (ChIP) analysis revealed that ethanol significantly prevented TCR inducible transcriptionally permissive histone H3 modifications at IL‐2 promoter in CD4+ T lymphocytes. Specifically, ethanol treatment inhibited phosphorylation of H3 serine 10 (H3S10ph) which then coordinately down regulated histone H3 lysine 4 tri‐methylation (H3K4Me3) and H3 lysine 9 acetylation (H3K9Ac). Notably, data showed that ethanol mediated transcriptional repression at IL‐2 promoter involves inhibition of Mitogen and Stress activated protein kinase (MSK‐1). Treatment of CD4+ T cells with MSK‐1 inhibitor further confirm the role of MSK‐1 mediated phosphorylation in regulating IL‐2 gene expression. Importantly, ethanol inhibited MSK‐1 activation via PP1 activation and could be reversed by okadaic acid‐phosphatase inhibitor treatment of CD4+ T lymphocytes. Overall, these observations suggest that, ethanol‐induced MSK‐1 inhibition and resultant decrease in promoter histone phosphorylation constitute a significant pathogenic mechanism underpinning the loss of IL‐2 expression and subsequent CD4+ T cell function associated with alcohol‐induced immune suppression. Support or Funding Information This work was supported by NIH grants.